Process for producing benzylamine compound

ABSTRACT

A process for producing a benzylamine compound represented by formula (2), which comprises reacting a benzaldehyde compound represented by formula (1) with an amino acid in the presence of an acid.

This Application is the U.S. National Stage, filed under 35 U.S.C. 371,of PCT/JP00/07692, filed Nov. 10, 2000.

TECHNICAL FIELD

The present invention relates to a novel process for producing abenzylamine compound important as an intermediate for the followingpyridazinone compound (3) useful as a medicine.

BACKGROUND ART

WO95/01343 and Japanese Unexamined Patent Publication JP-A-8-041033disclose the pyridazinone compound (3) as a useful medicine having abronchodilator action, an anti-allergic action and an antiplateletaction.

The compound (2), the important intermediate for synthesis of thepyridazinone compound (3), has been produced from isovanilline (4) inaccordance with the following reaction scheme.

The above-mentioned process comprises several steps and entailscumbersome operations.

Especially, the use of benzyloxycarbonyl (Z) as the protecting grouprequires not only additional two steps for its introduction and removalbut also expensive reagents such as benzyloxycarbonyl chloride (ZCl).Therefore, it is demanded to establish a process which uses noprotecting group from the operational and economical standpoints.

DISCLOSURE OF THE INVENTION

The present inventors proposed a direct conversion route from thecompound (1) to the benzylamine compound (2) as a solution to theabove-mentioned problems and, as a result of their extensive research,have found out that the compound (2) can be obtained in a high yield byusing various amino acids in the reaction.

Namely, the present invention provides a process for producing abenzylamine compound represented by formula (2), which comprisesreacting a benzaldehyde compound represented by formula (1) with anamino acid in the presence of an acid.

The novel process of the present invention is operationally advantageousbecause it can skip two steps in the conventional process. Besides, itis economically advantageous because it does not require an expensiveprotecting reagent.

BEST MODE FOR CARRYING OUT THE INVENTION

According to the present invention, the benzaldehyde compound (1)converts into the benzylamine compound (2) when heated with variousamino acids.

Preferable examples of the process of the present invention are recitedbelow.

(1)

A process for producing the benzylamine compound represented by formula(2), which comprises reacting the benzaldehyde compound represented byformula (1) with an amino acid in the presence of hydrochloric acid.

(2)

The process according to (1) wherein the amino acid is valine or2-aminoisobutyric acid.

(3)

The process for producing a benzylamine compound according to (1),wherein the reaction solvent is N,N-dimethylacetamide.

(4)

The process for producing a benzylamine compound according to (1) or(3), wherein the amount of hydrochloric acid is from two to threeequivalents of the amount of the benzaldehyde compound.

Now, the process will be described concretely.

The desired benzylamine compound represented by formula (2) isobtainable by heating the benzaldehyde compound represented by formula(1), an amino acid and an acid in a solvent.

If the heating is so conducted that the low-boiling components formed inthe reaction system evaporate, the same result (yield) can be obtainedwith a smaller amount of an amino acid than when the low-boilingcomponents are not evaporated.

The solvent may be, though there is no particular restriction, analcoholic solvent such as methanol or ethanol, a polar solvent such asN,N-dimethylacetamide or N,N-dimethylformamide or an aromatic organicsolvent such as toluene or dichlorobenzene. N,N-dimethylacetamide is thebest, but any other solvent may be used without particular restrictions.

Though there is no particular restrictions on the amount of a solvent,too much of a solvent tends to result in a lower yield, while in anexcessively small amount of a solvent, the operations in mass productiontend to be more difficult because stirring is tougher, and the producttends to be recovered as crystals with poor purity. Therefore, a solventis used in an amount of from 3 to 10 times the weight of the compound(1).

Though any acid that has a high acidity and does not cause sidereactions may be used without particular restrictions, as the acid, aninorganic acid such as hydrochloric acid or sulfuric acid or an organicacid such as methanesulfonic acid, trifluoromethanesulfonic acid orp-toluenesulfonic acid, preferably hydrochloric acid, may be mentioned.

With respect to the amount of an acid, at least 1 equivalent of an acid,based on the benzylamine compound (1), is required, but there is noparticular upper limit on the amount of the acid. However, the amount ofan acid is preferably from 2 to 3 equivalents based on the benzylaminecompound (1), because too much of an acid produces economical andoperational problems and the possibility of hydrolysis of the compound.

Because the above-mentioned amount means the amount of an acid presentin the reaction system, when a salt of the benzylamine compound (1) isused as a substrate, for example, the preferable amount of an externalacid to be added is from 1 to 2 equivalents.

As to specific examples of an acid to be added, for hydrochloric acid, 1mol/L hydrochloric acid-dioxane solution, 10% (w/w) hydrochloricacid-ethanol solution and 35% concentrated hydrochloric acid may bementioned as preferable examples, though there is no particularrestriction.

Any common amino acid may be used without any particular restriction.

Specific examples include glycine, alanine, valine, leucine, isoleucine,serine, threonine, cysteine, phenylalanine and 2-aminoisobutyric acid.Valine and 2-aminoisobutyric acid are preferred in view of yield andoperations.

Though there is no particular restriction on the amount of an aminoacid, if the amount is less than 2 moles based on the compound (1), theyield is likely to be low. However, heating the reaction system withevaporation of the low-boiling components formed in the reaction systemmakes it possible to reduce the amount of an amino acid to 1.5 moleswithout loss in yield. The upper limit is preferably from 1.5 moles to 3moles from the economical and operational standpoints, though there isno particular restriction.

As to the steric configuration of the amino acid, a d-, l- or dl-aminoacid may be used with no problem.

Though the reaction may be conducted in any temperature range thatallows the progress of the reaction and does not cause decompositionwithout any particular restriction, the reaction temperature range isfrom 100° C. to 250° C., preferably from 110° C. to 200° C.

Though the reaction time greatly depends on the reaction temperature, areaction time of from 0.5 to 10 hours, preferably from 1 to 5 hours orlonger is enough at a reaction temperature of 150° C.

The benzylamine compound (2) is obtained as a salt with the acid presentin the reaction system.

When the salt is crystalline, the salt of the benzylamine compound (2)can be recovered with high purity directly by filtration followed bywashing with a solvent such as diisopropyl ether.

Now, the present invention will be described in further detail withreference to Examples. However, the present invention is by no meansrestricted to these specific Examples. The seed crystals used in theExamples mean the compound (2).

EXAMPLE 1 Preparation of the Compound (2) Using dl-Valine inN,N-Dimethylacetamide (Without Evaporation of the Low-boilingComponents)

1 g of the monohydrochloride of the compound (1), 0.58 g of dl-valine, 6g of N,N-dimethylacetamide and 2.5 ml of 1 mol/L hydrochloricacid-dioxane solution were loaded into a 20 ml reactor and stirred at aninternal temperature of 150° C. for 2 hours.

The reaction mixture was cooled to 40° C., allowed to precipitatecrystals by addition of 20 g seed crystals, cooled again to an internaltemperature of 10° C. and maintained at the same temperature for 1 hour.

The crystals were recovered by filtration and washed with 1 g ofdiisopropyl ether to afford 0.74 g of the dihydrochloride of thebenzylamine compound (2).

m.p.:262° C. (decomposition).

EXAMPLE 2 Preparation of the Compound (2) Using 2-Aminoisobutyric Acidin N,N-dimethylacetamide (Without Evaporation of the Low-boilingComponents)

200 mg of the monohydrochloride of the compound (1), 57 mg of2-aminoisobutyric acid, 1.2 g of N,N-dimethylacetamide and 0.2 g of 10%(w/w) hydrochloric acid-ethanol solution were loaded into a 20 mlreactor and stirred at an internal temperature of 150° C. for 2 hours.

The reaction mixture was cooled until it precipitated crystals (to about40° C.), then further cooled to an internal temperature of 10° C. andmaintained at the same temperature for 1 hour.

The crystals were recovered by filtration and washed with 1 g ofdiisopropyl ether to afford 0.16 g of the desired dihydrochloride of thebenzylamine compound (2) (yield 73%).

m.p.: 262° C. (decomposition).

EXAMPLE 3 Preparation of the Compound (2) Using dl-Valine inN,N-Dimethylacetamide (With Evaporation of the Low-boiling Components)

7 g of the monohydrochloride of the compound (1), 3.04 g of dl-valine,28.89 g of N,N-dimethylacetamide and 1. of 35% concentrated hydrochloricacid were loaded into a 100 ml reactor and stirred at an internaltemperature of 110-120° C. for 2 hours while the low-boiling componentswere evaporated.

6.45 g of N,N-dimethylacetamide was evaporated under reduced pressure,and 10.5 g of isopropyl ether was added. Then, the mixture was cooled toan internal temperature of 5° C. and maintained at the same temperaturefor 1 hour.

The resulting crystals were recovered by filtration and washed with asolvent mixture of 3.3 g of N,N-dimethylacetamide and 3.3 g of isopropylether to afford 5 g of the desired dihydrochloride of the benzylaminecompound (2).

m.p.: 262° C. (decomposition).

Industrial Applicability

The present invention has established an operationally and economicallyadvantageous process for producing the compound (2) using no protectinggroup.

What is claimed is:
 1. A process for producing a benzylamine compoundrepresented by formula (2), which comprises reacting a benzaldehydecompound represented by formula (1) with an 5 amino acid in the presenceof an acid.


2. The process for producing a benzylamine compound according to claim1, wherein the acid is hydrochloric acid.
 3. The process for producing abenzylamine compound according to claim 2, wherein the amino acid isvaline or 2-aminoisobutyric acid.
 4. The process for producing abenzylamine compound according to claim 2, wherein the reaction solventis N,N-dimethylacetamide.
 5. The process for producing a benzylaminecompound according to claim 2 or 4, wherein the amount of hydrochloricacid is from two to three equivalents based on the benzaldehydecompound.